Abstract 20826: MicroRNA 205 Targets Low Density Lipoprotein Receptor Related Protein 1 in Liver of Diabetic Mice.
Introduction: LRP1 is a multifunctional cell surface receptor and in liver along with LDL receptor shares the endocytosis and subsequent degradation of TG-rich very low density lipoproteins and chylomicron remnants. MicroRNA 205 has been shown to down regulate the expression of LRP1 in both U87 and SK-LU-1 cells and decrease tumor cell migration.
Hypothesis: miR-205 is up regulated in the liver of diabetic mice and promotes hepatic steatosis, gluconeogenesis and plasma hyperlipidemia leading to early development of atherosclerosis.
Methods: NONcNZO10 (NZ10) mice with polygenic susceptibility to T2D or SWR/LtJ controls (40 per group) were fed Western (WD; high fat/carb) or Mediterranean (MD; high protein/unsaturated fat) diet for 25 weeks. Hepg2 cells were transfected with pre and anti miR-205 and gene and protein expression studied.
Results: SWR/LtJ (control) mice retained normal glycemic control and blood chemistry over 25 weeks on both diets. WD-fed NZ10 mice had increased plasma triglycerides (3-fold, p<0.001) insulin (1.8-fold. P<0.01) and severely impaired glucose tolerance relative to the MD groups (p<0.01). Gluconeogenic genes were increased significantly in NZ10 mice fed WD over those fed MD and control mice on either diet. MicroRNA profiling of 670 targets revealed that miR-205 was significantly up regulated (3.5 fold, p<0.001) in the liver of NZ10 mice fed WD over those on MD and control mice. Gene and protein expression studies confirmed the down regulation of LRP1 in liver of these diabetic mice. Oil red O staining for lipids showed increased fat accumulation in the livers of diabetic mice. Over expression of miR-205 in HepG2 cells significantly decreased the gene and protein expression of LRP1 and WNT5a and dampened AKT pathway.
Conclusion: miR-205 down regulates LRP1, impairing activation of WNT canonical pathway and leads to hepatic fat accumulation and increased plasma lipids disposing these mice to increased risk of atherosclerosis.
- © 2010 by American Heart Association, Inc.